Process for the production of 7-halogenosterols



Patented Sept. 18, 1951 PROCESS FOR THE PRODUCTION OF 7-HALOGENOSTEROLS Siegfried Pickholz, Grcenford, and Evan Roberts, London, England, assignors to Peboc Limited, Greenford, England, a British company No Drawing. Application March 20, 1950, Serial No. 150,814. In Great Britain March 24, 1949 14 Claims.

This invention relates to improvements in the production of sterols having a halogen atom in the '7-position, a double bond in the"5.6-position and a saturated open chain hydrocarbon residue in the 17 -position.

It is known (see for example, British patent specification No. 574,432 and copending application Serial No. 132,203 filed December 9, 1949), that sterols containing a halogen atom in the 7-position and a double bond in the 5.6-position can be dehydrohalogenated to produce 7-.dehydrosterols. 7-dehydrocholesterol which may be thus obtained is invaluable as a vitamin precursor. It is thus a matter of considerable importance to be able to produce 7-halogenosterols having a double bond in the 5.6-position smoothly and in good yield.

The known method for producing 7-halogenosterols depends upon the reaction discovered by K. Ziegler, Annalon, volume 551, pages 80 et seq. (1942) which is usually referred to as the Ziegler reaction. The Ziegler reaction depends upon the fact that certain compounds containing an active halogen atom viz. the N-chloroand bromo-amides of monocarboxylic acids and the corresponding imides of dicarboxylic acids can be used to halogenate compounds containing a methylene group adjacent to a double bond. A hydrogen atom of such a methylene group is replaced by the corresponding halogen.

It has been pointed out that in the case of a sterol which contains a double bond in the 5.6-position halogenation at the 4- and/or 7-positions is theoretically possible. Only the latter is, however, useful in obtaining the desired 'T-dehydrosterol's.

It has been realised for some time that unaccountable variations may be encountered during the course of carrying out this halogenation and several expedients have been proposed in efforts to overcome the difficulties that have been noted.- Thus the use of specific Ziegler reagents, such as certain substituted N-halogenobenzamides, has been recommended as well as the addition of specific additives, such as cyclohexene, and the catalytic action of light to initiate the reaction. The use of peroxides has'also been suggested. Some of these expedients may be capable of giving improved results under certain conditions but, in our experience, they do not appear to be generally applicable or involve working with compounds which themselves are not readily accessible or present other difliculties.

In our experience the essential factor in obtaining a satisfactory yield of 7-halogenosterol Ill is to provide conditions which enable the desired reaction to commence smoothly when the reactants are first brought together and to proceed with. moderate rapidity whilst providing conditions which substantially reduce the catalysis of an anionotropic effect 1. e. an allylic rearrangement. It has been found that this can be done by introducing into the reaction medium one or more of certain specific organic substances viz. pyridine, an alkyl pyridine, a polyalkylpyridine, an alkyl ester of a pyridine monocarboxylic acid, an amide ofsuch acid, urea or an alkyl ester of carbamic acid.

Accordingly, the present invention provides a process for the production of a 7-halogeno-3- sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the l'l-position which comprises monohalogenating a 3-sterol ester having a double bond in the 5.6-position and an open chain hydrocarbon residue in the 1'7-position with a Ziegler reagent under substantially non-acid conditions in the presence of pyridine, an alkyl pyridine, a polyalkyl pyridine, an alkyl ester of a pyridine monocarboxylic acid, an amide of a pyridine monocarboxylic acid, urea or an alkyl ester of carbamic acid.

The Ziegler reaction is carried out in an inert medium such as petroleum ether or carbon tetrachloride. The sterol ester having a double bond in the 5.6-position is dissolved therein and at least one of the named substances added, as well as the Ziegler reagent, which is preferably N bromosuccinimide or N bromophthalimide. The mixture is then heated under reflux until substantially all the Ziegler reagent has been used up: the reaction will, in general, be complete in not more than 15 minutes and preferably in 4 to 10 minutes.

The action of the named substances seems to be rather specific as substances which are regarded as chemically closely related either give no better yields than those reported in the conventional processes or, in some cases, appear to inhibit halogenation altogether. The above named substances do not appear to react with the Ziegler reagent.

As examples of sterols whose esters may be used there may be mentioned cholesterol, sitosterol and campesterol. The application of the invention in the smooth production of 7-halogenocholesterol in good yield and for direct conversion to 7-dehydrocholesterol is of considerable importance.

The process of the present invention may be combined with the known processes for the production of 7-dehydrosterols such as 'l-dehydrocholesterol by dehydrohalogenation or with the improved process described in copending application Serial No. 132,203 filed December 9, 1949, according to which dehydrohalogenation is effected at an elevated temperature in the presence of an acid acceptor and of an ester which is liquid at room temperature, has a boiling point under normal pressure ofat least 90 C., is unreactive with the l-halogenosterol ester, and with the '7-dehydrostero1 ester at the temperatures employed and in which the latter is not more than sparingly soluble at room temperature.

The following experiment is illustrative of the known process in which a time lag was observed before the reaction started and there was correspondingly a low yield of V-dehydrocholesterol.

12 gms. of cholesterol benzoate are dissolved in 110 ml. of petroleum ether (B. P. 60-80 C.) and refluxed for 45 minutes with 5.2 gms. of N-bromosuccinimide, cooled and filtered. Reaction did not seem to commence for about 35 minutes. 6 gms. of sodium carbonate and 60 ml. of ethyl benzoate are added to the filtrate and the petroleum ether distilled ofi at atmospheric pressure. The dehydrohalogenation is carried out at 125- 130 C. for 15 minutes. After cooling 60 ml. of water are added and the mixture is allowed to stand overnight at C. whereupon crystallisation occurs. The solid is filtered oif, washed with 25 ml. of Water and then with three 10 ml. portions of acetone. Saponification of the solid gave 2.9 gms. of 'l-dehydrocholesterol of 40% purity, corresponding to a 12% yield on the cho- I lesterol used.

The following examples illustrate the manner in which the invention may be carried into effect:

Example 1 12 gms. of cholesterol benzoate are dissolved in 110 ml. of petroleum ether (B. P. (SO-80 C.) to which is added 0.4 ml. of alpha-picoline and refiuxed for 10 minutes with 5.2 gms. of N-bromosuccinimide, cooled and filtered. The reaction appeared to commence as soon as the mixture was brought to reflux. 6 gms. of sodium carbonate and 60 ml. of ethyl benzoate are added to the filtrate and the petroleum ether distilled off at atmospheric pressure. The dehydrohalogenation is carried out at 130 C. for 15 minutes. After cooling 60 ml. of water are added and the mixture is allowed to stand overnight at 0 C. whereupon crystallisation occurs. The solid is filtered off, washed with 25 cos. of water and then with three 10 ml. portions of acetone. Saponification of the solid gave 4.3 gms. of 7-dehydrocholesterol of 90% purity corresponding'to a 40% yield on the cholesterol used.

Example 2 12.5 gms. of cholesterol benzoate are dissolved in 110 ml. of petroleum ether (B. P. 60-80 C.) and to it is added 5.4 gms. of N-bromo-succinimide, and 0.8 ml. of alpha-picoline. The mixture is refluxed for 12 minutes with vigorous stirring and then allowed to cool. 6 gms. of sodium carbonate and 60 ml. of ethyl benzoate are added to the filtrate and the petroleum ether distilled off at atmospheric pressure. The dehydrohalogenation is carried out at 130 C. for 15 minutes. After cooling 60 ml. of water are added and the product worked up as in Example 1. 4.6 gms. of 'T-dehydrocholesterol of 92% purity was obtained, corresponding to a 42% yield on the cholesterol used.

' 4 Example 3 12 gms. of cholesterol benzoate are dissolved in ml. of carbon tetrachloride to which is added 0.8 ml. of alpha-picoline and refluxed for five minutes with 5.2 gms. of N-bromo-succinimide. The yellow solution is allowed to cool and the succinimide filtered off. 6 gms. of sodium carbonate and 60 ml. of ethyl benzoate are added to the filtrate and the carbon tetrachloride removed under reduced pressure. The dehydrohalogenation is carried out at 125-l30 C. for 15 minutes. After cooling 60 ml. of water are added and the product Worked up as in Example 1. 3.8 gms. of 'T-dehydrocholesterol of 86% purity was obtained, corresponding to a 33.8% yield on the cholesterol used.

Example 4 12.5 gms. of cholesterol benzoate are dissolved in ml. of petroleum ether (B. P. 60-80 C.) and to it is added 5.4 gms. of N-bromo-succinimide and 0.8 ml. of pyridine, refluxed for 12 minutes, cooled and filtered. 6 gms. of sodium carbonate and 60 ml. of ethyl benzoate are added to the filtrate and the petroelum ether distilled off at atmospheric pressure. The dehydrohalogenation is carried out at 130 C. for 15 minutes. After cooling 60 ml. of water are added and the product worked up as in Example 1. 3.5 gms. of 'l-dehydrocholesterol of 92% purity is obtained, corresponding to a 32% yield on the cholesterol used.

Example 5 12.5 gms. of cholesterol benzoate are dissolved in 110 ml. of petroleum ether (B. P. (SO-80 C.) and to it is added 5.4 gms. of N-bromo-succinimide, and 1.2 m1. of ethyl picolinate the mixture refluxed for 12 minutes, cooled and filtered. The dehydrohalogenation was carried out with 6.5 gms. of sodium carbonate in 60 ml. of ethyl benzoate at -130 C. for 15 minutes. After cooling 60 m1. of water are added and the product worked up as in Example 1. 5.3 gms. of l-dehydrocholesterol of 63% purity is obtained, corresponding to a 33% yield on the cholesterol used.

Example 6 12.5 gms. of cholesterol benzoate are dissolved in 110 ml. of petroleum ether (B. P. 60-80 C.) and to it is added 5.4 gms. of N-bromo-succinimide and 1.3 gms. of urea, the mixture refluxed for 12 minutes, cooled and filtered. 6 gms. of sodium carbonate and 60 ml. of ethyl benzoate are added to the filtrate and the petroleum ether distilled off at atmospheric pressure. The dehydrohalogenation is carried out at C. for 15 minutes. After cooling 60 ml. of water are added and the product worked up as in Example 1. 3.6 gms. of 7-dehydrocholesterol, of 70% purity is obtained corresponding to a 25% yield on the cholesterol used.

Example 7 12.5 gms. of cholesterol benzoate are dissolved in 110 m1. of petroleum ether (B. P. 60-80 C.) and to it is added 5.4 gms. of N-bromo-succinimide and 1.5 gms. of nicotinamide, the mixture refluxed for 12 minutes, cooled and filtered. The dehydrohalogenation was carried out with 6.5 gms. of sodium carbonate in 60 ml. of ethyl benzoate at 125-130 C. for 15 minutes. After cooling 60 ml. of water are added and the product worked up as in Example 1. 4.6 gms. of 7-dehydrocholesterol of 78% purity is obtained, corresponding to a 35.5% yield on the cholesterol used.

Example 8 y 12.5 gins. ofcholesterol benzoate are dissolved in '110 ml. of petroleum ether (B. 60-80 'C.) and to it is .added 5.48 3 5.- 01" N-bromo-suc- ,cini'mideand 1.5'ml. oiethyl nicotinate the mixture refluxed for 1.2 minutes, cooled and filtered. The dehydrohalogenation was carried outwith 6.5 gms. of sodium carbonate in 60 ml. of ethyl benzoate at 125-130 C. for '15. minutes. .After cooling 60 ml. of water are added and'the product worked up as in Example 1. 4.8 gms. of"'. 7-dehydrocholesterol of 76% purity is obtained, corresponding to a 36.1% yieldon the cholesterol used.

Example 9 12.5 gm's. of cholesterol benzoate are dissolved in 100 m1. of petroleum ether (13. P. 80-100" C.) and to it is added 5.4 girls. of N-broinmsuccinimide and 1.2 ml. of beta-.pi'coline. The mixture is refluxed for. 4" minutes, cooled and filtered". 6.5 gms. of'sodium' carbonate and 60 ml. of ethyl benzoate are added to the filtrate and the petroleum ether distilled off at atmospheric pressure. The dehydrohalogenation is carried out at130 C. for minutes. After cooling 60ml. of 'Water are added and the mixture is allowed. to stand over: night at 0 C. whereuponv crystallisation occurs. The solid is filtered off, washed with cos. of water and then with three 10 ml..portions. of methanol. Saponification of the solid gavet2.9 gms. of 7-dehydrocholesterol. of 69% purityoorresponding to a 20.3% yield on the cholesterol used.

E w p e .1 .1.

' 12.5'gms. of cholesterol -benzoate are dissolved in 100 ml. of petroleum-ether (B. P. 80- 100 C.) and to it is added 5.4 gms; of- Nebromo-sum cinimide and 1.2 ml. of gamma picoline. The mixture'is'refiuxedfor e rninutes. cooledand filtered. 6;.5 gins. of sodium carbonate and 60 ml. of ethyl benzoate are added tothefiltrate and the petroleum. ether distilled off at atmospheric pressure; The dehydrohalogenation isicarried outat 130 C.

for 15 minutes. After cooling 60 ml. of-water are r added and theproduct worked upas in Example 1. 3.0 gms. of T-dehydrocholesterol of'.7 purity was obtained, corresponding to a 21.0% yield on the cholesterol used.

Example 11 g 12.5 gms. of cholesterol benzoate are dissolved 111-115 ml. of petroleum ether (B.1P; 60-80"- C.)

and to it is added 5.4 gins. orN-bromoi-esuccinimide and 1.2 ml. of gamma-picoline..-'Ilhe mixture-is refiuxed'for 15 minutes, cooled and filtered.

Example 1 2 12.5 gms. or cholesterol henz oate-ar e dissolved in 115 ml. of petroleum ether (B. P. GO-808C.)

and to it is added 5.4 gms. of N-bromosum.

cinimide-and 1.5; ml. of -symcollidi-ne.- The mixture is refluxed for 40 minutes, cooled and filtered. 6.5 gms. of sodium carbonate and 69 ml. of ethyl benzoate added to the filtrate and .the petroleum ether distilled oil at atmospheric pressure.

6: The dehydrohalogenation is carried out'at 130 Q. for 1-5 minutes. AftercoolingGO ml. 'ofwater: are added and the product worked up as in Example 1. 4.4 gms. of 'I-dehy-drocholesterol of '70% purity was obtained;corresponding to a 30.8% yield on the cholesterol used.

Example 13 I 12.5 gms. of cholesterol benzoate are dissolved in 100 m1. of petroleum ether (B. P. C.) and to-lt is added 5.4 gmswof N-bromo-succinimide and 1.5 ml. of symcollidine. The mixtureis refluxed for 6 minutes, cooled and filtered. 6.5 gms. of sodium carbonate and toy m1. of-jethyl benzoate are added to the filtrate and the {petroleiun ether distilled oil at atmospheric pressure. The dehydrohalogenation is carried out. at 130C. for 15 minutes. After cooling 60 ml. of water are added and the product workediupas in Example -1. 4.7 gins. of 7,-dehydrocholesterol of 80% purity was obtained, corresponding to a 37.6% yield on the cholesterol used.

Example 14 g 12.5 gms. of cholesterol benzoate are dissolved in ml. of petroleum ether (B. P. 60-80- "-.C.) and to it is added 5.4 guns. of N-bromo-succiriimide and 1.5 gms. of urethane. The mixture is refluxed for, 15 minutes, cooled and. filterect' 6 gms. of sodiumcarbonate and 60 ml. of ethyl bonzoate are added to the filtrate and the petroleum ether distilled off at atmospheric pressure. The dehydrohalogenation is carried out at-.130 C. for 1-5:minutes. After cooling 60. ml. of water are added and the product worked up as inkExe ample 1. 3.4. gills; of 'l-dehydrocholesterol of 74% purity was obtained, corresponding to a 25.1% yield on the cholesterol used.

Example 15 12.5 gms. of cholesterol benzoate are dissolyed in 110ml. of. petroleum ether (B. P. 60-80EC.) and to it is added 6.8 guns. of N-bromo-phthalimide and 1.0 ml. alpha-picoline. The mixtureis refluxed for 12 minutes, cooled and filteredL-fifi gins. of sodium carbonate and 60 ml. of ethyl benzoate. are added tothe filtrate. and the petroleumether distilled on at atmospheric pressure. The dehydrohalogenation is carried out at C. for 15 minutes. After cooling 60 ml. of water are added and the product worked up as in EX- ample 1. 4.9 gins. of '7-dehydrocholesterol of 78% purity was obtained corresponding to a 36.14% yield on the cholesterol used.

Example 16 11.0 gms. of cholesterol acetate are dissolved in 100 ml. of petroleum ether (B. P. 60-80 C.) and to it is added 5.4 gms. of N -bromo-succi-nim-' ide and 1.0 ml. of alpha-picoline. The mixture is refluxed for 12 minutes, cooled and filtered; 615 gms. of sodium carbonate and 60 ml. of dimethyl phthalate are added to the filtrate and the petroleum" ether distilled off at atmospheric pressure. The-'dehydrohalogenation is carried out at 130? C. for l5-minutes. After cooling-60 ml. of water are added and the product worked; up as I in Earample l. 3.6 gms. of"7-dehydrocho1ester0l of'8'5% purity was obtained, corresponding to a 30.6% yield on the cholesterol used. a VI 7 Example 17 v V I 11.0 gms. of cholesterol: acetate areldissolvediin 100 ml; of. petroleum .ether (B. P. 60-80": (7.) and .toiit is added 6.8 gms.of.N-bromo-phthalimide and 1.0 ml. of alpha-picoline- The mixture is refluxed for 12 minutes, cooled and filtered. 6.5 'gms. of sodium carbonate and 60 ml. of dimethyl phthalate are added to the filtrate and the petroleum ether distilled ofi at atmospheric pressure. The dehydrohalogenation is carried out at 130 C. for 15 minutes. After cooling 60 ml. of water are added and the product worked up as in Example l. 3.4 gms. of '7 -dehydrocholesterol of 82% purity was obtained, corresponding to 27.9% yield on the cholesterol used.

In the above examples the yield of 7-dehydrosterol under similar conditions of dehydrohalogenation is taken as providing a measure of the success of the bromination in the correct position. The degree of purity and the overall yield are two factors of considerable importance 'when the product is subsequently to be subjected to irradiation. It will be noted that when the bromination procedure is carried out in accordance with the present invention and the dehydrohalogena'tion in accordance with that of copending application Serial No. 132,203 filed December 9, 1949, yields of the 'Y-dehydrosterol (based on the sterol used) as high as 30-40% with an overall purity of 90% and even higher can be obtained. From this point of view, theuse of alpha-picoline has much to commend it. c In general the amount of added substance is less than one mol based upon the sterolester employed: it is preferred to have present 0.2-0.5 mol of the added substance for each mol of the 3-sterol ester.

Some excess of the Ziegler reagent may be employed. This may be as much as 20-30% based upon the sterol ester. 1 It has been noted that alpha-picoline is the preferred base for use in the process of the present invention. The use of thiourea, quinoline and quinaldine gave products from which about 70% of unchanged sterol ester could be recovered and very little l-dehydrocholesterol was separated. Guanidine carbonate, dicyandiamide and hexamethylene tetramine behaved similarly whilst dimethylaniline, acetonitrile, nicotine and triethylamine react preferentially with the Ziegler reagent. I

1. A process for the production of a 7-halogeno- 3-sterol ester having a double bond in the 5.6- position and a saturated open chain hydrocarbon residue in the l'l-position which comprises monohalogenating a 3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 17-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboXylic acid amides and imides under substantially non-acid conditions in the presence of a substance selected from the group consisting of pyridine, alkyl pyridines, polyalkylpyridines, alkyl esters of pyridine monocarboxylic acids, amides of pyridine monocarboxylic acids, urea and alkyl esters of carbamic acid.

2. A process for the production of a- 7-halogeno-3-sterol ester having a double bond in the 5.6-position and asaturated open chain hydrocarbon residue in the 17-position which comprises mono-halogenating a 3-sterol ester having a double bond in the 5.6-position and a saturated 'open chain hydrocarbon residue in the 17-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides'under substantially non-acid conditions in the presence of 0.2 to .5 mol for each mol of 3-sterol ester of a substance selected from the group consisting of pyridine, alkyl pyridines, polyalkylpyridines, alkyl esters of pyridine monocarboxylic acids, amides of pyridine monocarboxylic acids, urea and alkyl esters of carbamic acid.

3. The process according to claim 2 in which an excess of a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides, based upon the B-sterol ester, is employed.

4. A process for the production of a l-halogeno-B-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the l'l-position which comprises mono-halogenating a 3-sterol ester having a double bond in the 5.6-position and an open chain hydrocarbon residue in the l'l-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially non-.- acid conditions in the presence of 0.2-0.5 mol of alpha-picoline for each mol of the 3-sterol ester.

5. A process for the production of a 7-halogeno- 3-sterol ester having a double bond in the 5.6- position and a saturated open chain hydrocarbon residue in the 1'7-position which comprises monohalogenating a 3-sterol ester having a double bond in the 5.6-position and an open chain hydrocarbon residue in the l'l-position with a halogenating agent selected from the group consisting of N- chloro and N-bromo carboxylic acid amides and imides under substantially non-acid conditions in the presence of 0.2-0.5 mol of pyridine for each mol of the 3-sterol ester.

6. A process for the production of a 7-halogeno-3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 17-position which comprises mono-halogenating a -sterol ester having a double bond in the 5.6-position and an open chain hydrocarbon residue in the 17-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially non-acid conditions in the presence of 0.2-0.5 mol of ethyl nicotinate for each mol of the 3-sterol ester.

7. A process for the production of a '7-halogeno-S-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon/residue in the 17-position which comprises mono-halogenating a 3-sterol ester havin a double bond in the 5.6-position and an open chain hydrocarbon residue in the l'l-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially nonacid conditions in the presence of 0.2-0.5 mol of ethyl picolinate for each mol of the 3-stero1 ester.

8. A process for the production of a l-halogeno-3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 17-position which comprises mono-halogenating a 3-stero1 ester having a double bond in the 5.6-position and an open chain hydrocarbon residue in the l'l-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially non-acid conditions in the presence of 0.2-0.5 mol of symmetrical collidine for each mol of the 3-sterol ester.

9. A process for the production of a 7-halogeno-3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydro carbon residue in the 17-positi0n which comprises heating a 3-stero1 ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 17-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially non-acid conditions in the presence of not more than 0.5 mol for each mol of sterol ester of a substance selected from the group consisting of pyridine, alkyl pyridines, polyalkylpyridines, alkyl esters of pyridine monocarboxylic acids, amides of pyridine monocarboxylic acids, urea and alkyl esters of carbamic acid.

10. A process for the production of a 7-ha1ogeno-3-stero1 ester having a double bond in the 5.6-psition and a saturated open chain hydrocarbon residue in the 17-position which comprises heating a 3-stero1 ester having a double bond in the 5.6p0sition and a saturated open chain hydrocarbon residue in the 17-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially non-acid conditions in the presence of not more than 0.5 mol for each mol of sterol ester of alpha-picoline.

11. A process for the production of a 7-halogeno-3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 17-position which comprises heating a 3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 1'7-position with a halogenated agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially nonacid conditions in the presence of not more than 0.5 mol for each mol of sterol ester of pyridine.

12. A process for the production of a 7-halogeno-3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 17-position which comprises heating a 3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 17-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially non-acid conditions in the presence of not more than 0.5 mol for each mol of sterol ester of of ethyl nicotinate.

13. A process for the production of a 7-halogeno-3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 17-position which comprises heating a 3-sterol ester having a double bond in the 5.6-position and a saturated open chain hydrocarbon residue in the 17-position with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially non-acid conditions in the presence of not more than 0.5 mol for each mol of sterol ester 'of ethyl picolinate.

with a halogenating agent selected from the group consisting of N-chloro and N-bromo carboxylic acid amides and imides under substantially non-acid conditions in the presence of not more than 0.5 mol for each mol of sterol ester of symmetrical collidine.

SIEGFRIED PICKHOLZ. EVAN ROBERTS.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,498,890 Bernstein Feb. 21, 1950 

1. A PROCESS FOR THE PRODUCTION OF A 7-HALOGENO3-STEROL ESTER HAVING A DOUBLE BOND IN THE 5.6POSITION AND A SATURATED OPEN CHAIN HYDROCARBON RESIDUE IN THE 17-POSITION WHICH COMPRISES MONOHALOGENATING A 3-STEROL ESTER HAVING A DOUBLE BOND IN THE 5.6-POSITION AND A SATURATED OPEN CHAIN HYDROCARBON RESIDUE IN THE 17-POSITION WITH A HALOGENATING AGENT SELECTED FROM THE GROUP CONSISTING OF N-CHLORO AND N-BROMO CARBOXYLIC ACID AMIDES AND IMIDES UNDER SUBSTANTIALLY NON-ACID CONDITIONS IN THE PRESENCE OF A SUBSTANCE SELECTED FROM THE GROUP CONSISTING OF PYRIDINE, ALKYL PYRIDINES, POLYALKYLPYRIDINES, ALKYL ESTERS OF PYRIDINE MONOCARBOXYLIC ACIDS, AMIDES OF PYRIDINE MONOCARBOXYLIC ACIDS, UREA AND ALKYL ESTAERS OF CARBAMIC ACID. 